1. Field of the Invention
The present invention relates to novel nonpolymeric compounds and compositions that form liquid, high viscosity materials suitable for the delivery of biologically active substances in a controlled fashion, and for use as medical or surgical devices. The materials can optionally be diluted with a solvent to form a material of lower viscosity, rendering the material easy to administer. This solvent may be water insoluble or water soluble, where the water soluble solvent rapidly diffuses or migrates away from the material in vivo, leaving a higher viscosity liquid material.
2. Description of Related Art
There has been extensive research in the area of biodegradable controlled release systems for bioactive compounds. Biodegradable matrices for drug delivery are useful because they obviate the need to remove the drug-depleted device.
The most common matrix materials for drug delivery are polymers. The field of biodegradable polymers has developed rapidly since the synthesis and biodegradability of polylactic acid was reported by Kulkarni et al., in 1966 (xe2x80x9cPolylactic acid for surgical implants,xe2x80x9d Arch. Surg., 93:839). Examples of other polymers which have been reported as useful as a matrix material for delivery devices include polyanhydrides, polyesters such as polyglycolides and polylactide-co-glycolides, polyamino acids such as polylysine, polymers and copolymers of polyethylene oxide, acrylic terminated polyethylene oxide, polyamides, polyethylenes, polyorthoesters, polyacrylonitriles, and polyphosphazenes. See, for example, U.S. Pat. Nos. 4,891,225 and 4,906,474 to Langer (polyanhydrides), U.S. Pat. No. 4,767,628 to Hutchinson (polylactide, polylactide-co-glycolide acid), U.S. Pat. No. 4,530,840 to Tice, et al. (polylactide, polyglycolide, and copolymers), and U.S. Pat. No. 5,234,520 (Dunn et al., biodegradable polymers for controlled delivery in treating periodontal disease).
Degradable materials of biological origin are well known including, for example, crosslinked gelatin. Hyaluronic acid has been crosslinked and used as a degradable swelling polymer for biomedical applications (U.S. Pat. No. 4,957,744 to Della Valle et al.; (1991) xe2x80x9cSurface modification of polymeric biomaterials for reduced thrombogenicity,xe2x80x9d Polym. Mater. Sci. Eng., 62:731-735]).
Biodegradable hydrogels have also been developed for use in controlled drug delivery as carriers of biologically active materials such as hormones, enzymes, antibiotics, antineoplastic agents, and cell suspensions. Temporary preservation of functional properties of a carried species, as well as the controlled release of the species into local tissues or systemic circulation, have been achieved. See for example, U.S. Pat. No. 5,149,543 to Cohen. Proper choice of hydrogel macromers can produce membranes with a range of permeability, pore sizes and degradation rates suitable for a variety of applications in surgery, medical diagnosis and treatment.
Many dispersion systems are currently in use as, or being explored for use as, carriers of substances, particularly biologically active compounds. Dispersion systems used for pharmaceutical and cosmetic formulations can be categorized as either suspensions or emulsions. Suspensions are defined as solid particles ranging in size from a few nanometers up to hundreds of microns, dispersed in a liquid medium using suspending agents. Solid particles include microspheres, microcapsules, and nanospheres. Emulsions are defined as dispersions of one liquid in another, stabilized by an interfacial film of emulsifiers such as surfactants and lipids. Emulsion formulations include water in oil and oil in water emulsions, multiple emulsions, microemulsions, microdroplets, and liposomes. Microdroplets are unilamellar phospholipid vesicles that consist of a spherical lipid layer with an oil phase inside, as defined in U.S. Pat. Nos. 4,622,219 and 4,725,442 issued to Haynes. Liposomes are phospholipid vesicles prepared by mixing water-insoluble polar lipids with an aqueous solution. The unfavorable entropy caused by mixing the insoluble lipid in the water produces a highly ordered assembly of concentric closed membranes of phospholipid with entrapped aqueous solution.
U.S. Pat. No. 4,938,763 to Dunn, et al., discloses a method for forming an implant in situ by dissolving a non-reactive, water insoluble thermoplastic polymer in a biocompatible, water soluble solvent to form a liquid, placing the liquid within the body, and allowing the solvent to dissipate to produce a solid implant. The polymer solution can be placed in the body via syringe. The implant can assume the shape of its surrounding cavity. In an alternative embodiment, the implant is formed from reactive, liquid oligomeric polymers which contain no solvent and which cure in place to form solids, usually with the addition of a curing catalyst.
While a number of materials have been evaluated for use in the controlled delivery of substances, there remains a need to provide more simple systems with low toxicity for the controlled delivery of substances. The delivery systems described above, for example, require the preparation of polymers and loaded polymeric matrices, or hydrogels, or other complex or fragile compositions. In particular, there is a need to provide a liquid-based delivery system that is easily formulated with a substance to be delivered and easily administered.
Therefore, it is an object of the invention to provide a simple system for the delivery of substances.
It is another object of the invention to provide a liquid-based delivery system that is easily formulated with a substance to be delivered and easily administered.
It is another object of the present invention to provide a method for the controlled delivery of substances in a simple liquid-based system.
The invention relates to compounds, and to compositions containing them, as well as to methods of using these compounds and compositions as delivery vehicles, for example as controlled delivery vehicles, for substances, such as bioactive substances. The invention also relates to these compounds, compositions, and methods of using them as medical or surgical devices, such as medical or surgical implants, films, or graft compositions. The compositions are generally in liquid form, and contain at least one non-water soluble, high viscosity, liquid carrier material comprising a nonpolymeric ester or mixed ester of one or more carboxylic acids, having a viscosity of at least 5,000 cP at 37xc2x0 C., that does not crystallize neat under ambient or physiological conditions. The compositions can be dissolved in a physiologically acceptable solvent to lower their viscosity, rendering them easier to administer. After administration of compositions containing water-soluble solvents, however, the solvent diffuses or otherwise dissipates away from the material, which thus increases significantly in viscosity, and thereby forms a controlled release matrix for a bioactive substance, or a medical or surgical implant, film, or graft. Non-water soluble solvents may also be used, but will diffuse away from the nonpolymeric ester or mixed ester much more slowly.
Dissolution in solvent is particularly useful with nonpolymeric esters or mixed esters having very high viscosities, e.g., on the order of 100,000 cP at 37xc2x0 C. Some nonpolymeric esters or mixed esters suitable for use in the invention, while having viscosities above 5,000 cP at 37xc2x0 C., are not as viscous, and may be administered neat, i.e., without the addition of a solvent.
In another aspect, the invention relates to a method of administering a biologically active substance to a plant or an animal (including humans) by administering to the plant or animal a composition containing a non-water soluble, high viscosity, liquid carrier material comprising a nonpolymeric ester or mixed ester of one or more carboxylic acids, having a viscosity of at least 5,000 cP at 37xc2x0 C., that does not crystallize neat under ambient or physiological conditions and a biologically active substance. The particular method of administration may vary, and may include topical, oral (e.g., as a solution, emulsion, or in a gelatin capsule), nasal, pulmonary, rectal, vaginal, or injectable routes for animals, and topical or injectable routes for plants.
In another aspect, the invention relates to a medical or surgical implant, film, or graft composition containing a non-water soluble, high viscosity, liquid carrier material comprising a nonpolymeric ester or mixed ester of one or more carboxylic acids, having a viscosity of at least 5,000 cP at 37xc2x0 C., that does not crystallize neat under ambient or physiological conditions.
In yet another aspect, the invention relates to a method for the in vivo formation of an implant, film, or graft in a patient in need thereof, including:
(1) contacting a mixture containing:
(a) a non-water soluble, high viscosity, liquid carrier material comprising a nonpolymeric ester or mixed ester of one or more carboxylic acids, having a viscosity of at least 5,000 cP at 37xc2x0 C., that does not crystallize neat under ambient or physiological conditions; and
(b) a solvent in which the non-polymeric, non-water soluble liquid carrier material is soluble; wherein the mixture has a viscosity of less than approximately 6000 cP at 37xc2x0 C.; with the tissue of the patient; and
(2) allowing the solvent to dissipate or diffuse into the tissue of the patient, thereby forming an implant, film, or graft of the non-polymeric, non-water soluble, high viscosity liquid carrier material. In an even more particular aspect of the invention, the mixture has as viscosity of less than approximately 4,000 cP, even more particularly, less than approximately 1,000 cP, at 37xc2x0 C.
In yet another aspect, the invention relates to novel compounds having a structure selected from the group consisting of: 
wherein R1, R2, and R3 are independently selected from the group consisting of hydrogen, alkanoyl having 2 to 6 carbons, hydroxy-substituted alkanoyl having 2 to 6 carbons, and acyloxy-substituted alkanoyl having 2 to 6 carbons, wherein n is between 1 and 20, and wherein at least one of R1, R2, and R3 is other than hydrogen; 
wherein n is an integer between 4 and 8, and R1 and R2 are independently selected from the group consisting of hydrogen, alkanoyl having 2 to 6 carbons, hydroxy-substituted alkanoyl having 2 to 6 carbons, and acyloxy-substituted alkanoyl having 2 to 6 carbons, and wherein at least one of R1 and R2 is other than hydrogen; 
wherein R1, R2, R3, R4, and R5 are independently selected from the group consisting of hydrogen, alkanoyl having 2 to 6 carbons, hydroxy-substituted alkanoyl having 2 to 6 carbons, and acyloxy-substituted alkanoyl having 2 to 6 carbons, and wherein at least one of R1, R2, R3, R4, and R5 is other than hydrogen; 
wherein R1, R2, R3, R4, R5, and R6 are independently selected from the group consisting of hydrogen, alkanoyl having 2 to 6 carbons, hydroxy-substituted alkanoyl having 2 to 6 carbons, and acyloxy-substituted alkanoyl having 2 to 6 carbons, and wherein at least one of R1, R2, R3, R4, R5, and R6 is other than hydrogen; 
wherein R1, R2, R3, and R4 are independently selected from the group consisting of hydrogen, alkanoyl having 2 to 6 carbons, hydroxy-substituted alkanoyl having 2 to 6 carbons, and acyloxy-substituted alkanoyl having 2 to 6 carbons, and wherein at least one of R1, R2, R3, and R4 is other than hydrogen.
In a more particular aspect, the novel compound has the structure: 
wherein R1, R2, R3, and R4 are independently selected from the group consisting of hydrogen, alkanoyl having 2 to 6 carbons, hydroxy-substituted alkanoyl having 2 to 6 carbons, and acyloxy-substituted alkanoyl having 2 to 6 carbons, and wherein at least one of R1, R2, R3, and R4 is other than hydrogen.
The liquid compositions of the invention can be used in any of the utilities or applications disclosed for HVLCM or LVLCM in U.S. Ser. No. 08/944,022, U.S. Ser. No. 478,450, and U.S. Ser. No. 08/474,337, now U.S. Pat. No. 5,747,058, the entire contents of each of which are hereby incorporated by reference.